Pyrazine derivatives and use as PI3K inhibitors

Abstract

The present invention is related to pyrazine derivatives of Formula (I) in particular for the treatment and/or prophylaxis of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, transplantation, graft rejection or lung injuries.

We claim: 
     
       1. A compound according to Formula (I), 
       
         
           
           
               
               
           
         
         wherein: 
         A is nitrogen and B, D and E are carbon; or A, B and E are carbon and D is nitrogen; 
         R l  is H, halogen, nitro, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl or optionally substituted C 2 -C 6 -alkynyl; 
         R 2  is H, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl or optionally substituted C 2 -C 6 -alkynyl; 
         R 3  is H, halo, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted alkoxy, optionally substituted aryl or optionally substituted heteroaryl; 
         R 4  is optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8  cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl C 1 -C 6 -alkyl, optionally substituted heteroaryl C 1 -C 6 -alkyl, optionally substituted C 3 -C 8  cycloalkyl optionally substituted C 1 -C 6 -alkyl, optionally substituted heterocycloalkyl C 1 -C 6 -alkyl, optionally substituted aryl C 2 -C 6 -alkenyl or optionally substituted heteroaryl C 2 -C 6 -alkenyl; 
         n is an integer selected from 0, 1, 2, 3 and 4; 
         an optionally substituted group is substituted with from 1 to 5 substituent's selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl, C 1 -C 6 -alkyl cycloalkyl, C 1 -Co-alkyl heterocycloalkyl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, aryl, carbamate, heteroaryl, sulfinyl, sulfonyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto and nitro; 
         with the first proviso that when R 4  is thiophenyl, it is not selected from the group consisting of: unsubstituted thiophenyl, unsubstituted chloro-5-thiophenyl and unsubstituted bromo-5thiophenyl; with the second proviso that when R 4  is a phenyl, it is a mono-substituted phenyl that is not selected from the group consisting of: p-bromo phenyl; p-methoxy phenyl; p- ethoxy phenyl; o-, m- or p-chloro phenyl; m- or p-methyl phenyl; o- or p-fluoro phenyl; o-CF3- phenyl; p- or m-nitro phenyl; p-NHAc-phenyl and p-amino phenyl; or it is a multi-substituted phenyl, that is not an unsubstituted bi-substituted phenyl selected from the group consisting of: 
         m-, p-dimethyl phenyl; m-, m-dimethyl phenyl; o-, p-dimethyl phenyl; o-, m-dimethyl phenyl; o-methyl p-fluoro phenyl; m-, m-dichloro phenyl; o-, m-dichloro phenyl; p-chloro m-nitro phenyl and o-ethoxy m-bromo phenyl; 
         with the final proviso that wherein R 4  is a 1,4 benzodioxin it is a substituted benzodioxin; 
         or an optically active form or a pharmaceutically acceptable salt thereof. 
       
     
     
       2. The compound according to  claim 1 , wherein R 1  is H or halogen. 
     
     
       3. The compound according to  claim 1 , wherein R 2  is methyl or substituted methyl. 
     
     
       4. The compound according to  claim 1 , wherein R 3  is H, alkoxy or substituted alkoxy. 
     
     
       5. The compound according to  claim 1 , wherein R 3  is halo, optionally substituted aryl or optionally substituted heteroaryl. 
     
     
       6. The compound according to  claim 1 , wherein R 4  is optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted aryl C 1 -C 6 -alkyl or optionally substituted heteroaryl C 1 -C 6 -alkyl. 
     
     
       7. The compound according to  claim 1 , wherein R 4  is optionally substituted aryl or optionally substituted heteroaryl. 
     
     
       8. The compound according to  claim 1 , wherein R 1  is H or halogen; R 2  is substituted methyl; and R 3  is H or substituted alkoxy. 
     
     
       9. The compound according to  claim 1 , wherein R 1  is H or halogen; R 2  is methyl; R 3  is H or alkoxy. 
     
     
       10. The compound according to  claim 1 ,
 wherein: 
 A, B and E are carbon and D is nitrogen; 
 R 1  is H, halogen, nitro, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl or optionally substituted C 2 -C 6 -alkynyl; 
 R 2  is H, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl or optionally substituted C 2 -C 6 -alkynyl; 
 R 3  is H, halo, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted alkoxy, optionally substituted aryl or optionally substituted heteroaryl; 
 R 4  is optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8  cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl C 1 -C 6 -alkyl, optionally substituted heteroaryl C 1 -C 6 -alkyl, optionally substituted C 3 -C 8  cycloalkyl optionally substituted C 1 -C 6 -alkyl, optionally substituted heterocycloalkyl C 1 -C 6 -alkyl, optionally substituted aryl C 2 -C 6 -alkenyl or optionally substituted heteroaryl C 2 -C 6 -alkenyl; 
 n is an integer selected from 0, 1, 2, 3 and 4; 
 an optionally substituted group is substituted with from 1 to 5 substituents selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl, C 1 -C 6 -alkyl cycloalkyl, C 1 -C 6 -alkyl heterocycloalkyl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, aryl, carbamate, heteroaryl, sulfinyl, sulfonyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto and nitro; 
 with the first proviso that when R 4  is thiophenyl, it is not selected from the group consisting of: unsubstituted thiophenyl, unsubstituted chloro-5-thiophenyl and unsubstituted bromo-5-thiophenyl; with the second proviso that when R 4  is a phenyl, it is a mono-substituted phenyl that is not selected from the group consisting of: p-bromo phenyl; p-methoxy phenyl; p- ethoxy phenyl; o-, m- or p-chloro phenyl; m- or p-methyl phenyl; o- or p-fluoro phenyl; o-CF3- phenyl; p- or m-nitro phenyl; p-NHAc-phenyl and p-amino phenyl; or it is a multi-substituted phenyl, that is not an unsubstituted bi-substituted phenyl selected from the group consisting of: m-, p-dimethyl phenyl; m-, m-dimethyl phenyl; o-, p-dimethyl phenyl; o-, m-dimethyl phenyl; o-methyl p-fluoro phenyl; m-, m-dichloro phenyl; o-, m-dichloro phenyl; p-chloro m-nitro phenyl and o-ethoxy m-bromo phenyl; 
 with the final proviso that wherein R 4  is a 1,4 benzodioxin it is a substituted benzodioxin; 
 or an optically active form or a pharmaceutically acceptable salt thereof. 
 
     
     
       11. The compound according to  claim 10 , wherein R 1  is H or halogen. 
     
     
       12. The compound according to  claim 10 , wherein R 2  is methyl or substituted methyl. 
     
     
       13. The compound according to  claim 10 , wherein R 3  is H, alkoxy or substituted alkoxy. 
     
     
       14. The compound according to  claim 10 , wherein R 3  is halo, optionally substituted aryl or optionally substituted heteroaryl. 
     
     
       15. The compound according to  claim 10 , wherein R 4  is optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted aryl C 1 -C 6 -alkyl or optionally substituted heteroaryl C 1 -C 6 -alkyl. 
     
     
       16. The compound according to  claim 10 , wherein R 4  is optionally substituted aryl or optionally substituted heteroaryl. 
     
     
       17. The compound according to  claim 10 , wherein R 1  is H or halogen; R 2  is substituted methyl; and R 3  is H or substituted alkoxy. 
     
     
       18. The compound according to  claim 10 , wherein R 1  is H or halogen; R 2  is methyl; R 3  is H or alkoxy. 
     
     
       19. The compound according to  claim 1 , wherein:
 A is nitrogen and B, D and E are carbon; 
 R 1  is H, halogen, nitro, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl or optionally substituted C 2 -C 6 -alkynyl; 
 R 2  is H, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl or optionally substituted C 2 -C 6 -alkynyl; 
 R 3  is H, halo, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted alkoxy, optionally substituted aryl or optionally substituted heteroaryl; 
 R 4  is optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8  cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl C 1 -C 6 -alkyl, optionally substituted heteroaryl C 1 -C 6 -alkyl, optionally substituted C 3 -C 8  cycloalkyl optionally substituted C 1 -C 6 -alkyl, optionally substituted heterocycloalkyl C 1 -C 6 -alkyl, optionally substituted aryl C 2 -C 6 -alkenyl or optionally substituted heteroaryl C 2 -C 6 -alkenyl; 
 n is an integer selected from 0, 1, 2, 3 and 4; 
 an optionally substituted group is substituted with from 1 to 5 substituents selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl, C 1 -C 6 -alkyl cycloalkyl, C 1 -C 6 -alkyl heterocycloalkyl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, aryl, carbamate, heteroaryl, sulfinyl, sulfonyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto and nitro; 
 with the first proviso that when R 4  is thiophenyl, it is not selected from the group consisting of: unsubstituted thiophenyl, unsubstituted chloro-5-thiophenyl and unsubstituted bromo-5-thiophenyl; with the second proviso that when R 4  is a phenyl, it is a mono-substituted phenyl that is not selected from the group consisting of: p-bromo phenyl; p-methoxy phenyl; p- ethoxy phenyl; o-, m- or p-chloro phenyl; m- or p-methyl phenyl; o- or p-fluoro phenyl; o-CF3- phenyl; p- or m-nitro phenyl; p-NHAc-phenyl and p-amino phenyl; or it is a multi-substituted phenyl, that is not an unsubstituted bi-substituted phenyl selected from the group consisting of: 
 m-, p-dimethyl phenyl; m-, m-dimethyl phenyl; o-, p-dimethyl phenyl; o-, m-dimethyl phenyl; o-methyl p-fluoro phenyl; m-, m-dichloro phenyl; o-, m-dichloro phenyl; p-chloro m-nitro phenyl and o-ethoxy m-bromo phenyl; 
 with the final proviso that wherein R 4  is a 1,4 benzodioxin it is a substituted benzodioxin; 
 or an optically active form or a pharmaceutically acceptable salt thereof. 
 
     
     
       20. The compound according to  claim 19 , wherein R 1  is H or halogen. 
     
     
       21. The compound according to  claim 19 , wherein R 2  is methyl or substituted methyl. 
     
     
       22. The compound according to  claim 19 , wherein R 3  is H, alkoxy or substituted alkoxy. 
     
     
       23. The compound according to  claim 19 , wherein R 3  is halo, optionally substituted aryl or optionally substituted heteroaryl. 
     
     
       24. The compound according to  claim 19 , wherein R 4  is optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted aryl C 1 -C 6 -alkyl or optionally substituted heteroaryl C 1 -C 6 -alkyl. 
     
     
       25. The compound according to  claim 19 , wherein R 4  is optionally substituted aryl or optionally substituted heteroaryl. 
     
     
       26. The compound according to  claim 19 , wherein R 1  is H or halogen; R 2  is substituted methyl; and R 3  is H or substituted alkoxy. 
     
     
       27. The compound according to  claim 19 , wherein R 1  is H or halogen; R 2  is methyl; R 3  is H or alkoxy. 
     
     
       28. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent or excipient and the compound according to  claim 1 .